It is now known that two common amino acids, glutamate and aspartate, are the major excitatory neurotransmitters in the mammalian brain. It is estimated that between 30 and 40% of all brain neurons use these two agents to communicate. Glutamate and aspartate are referred to as excitatory amino acids (EAA's). After physical trauma or stroke (ischemia), nerve cells which use the EAA's as their neurotransmitters become hyperactive and begin to release very large quantities of the EAA transmitters. This process results in the exhaustion and death of the neurons from EAA overstimulation. The two natural neurotransmitters, glutamate and aspartate, actually become toxins in the injured brain, due to their increased release from neurons. This phenomenon has been termed excitotoxicity.
U.S. Pat. No. 4,806,543 discloses the use of dextrorotatory opiate agonists such as dextrorphan and dextromethorphan to protect against this phenomenon in a number of acute and chronic neurologic disorders, including ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).
Dextromethorphan is known to bind to distinct receptors in the central nervous system (Tortella et al., TIPS 10:501-507, 1989; Craviso and Musacchio, Mol. Pharmacol. 23:629-640, 1983). Although these receptors have not been fully characterized, they may be responsible for the unique anticonvulsant and neuroprotective effects reported for this drug (Leander, Epilepsy Res. 4:28-33, 1989; Koyuncuoglu and Saydam, Intnl. J. Clin. Pharmacol. Ther. Tox. 28:147-152, 1990; Ferkany et al., Eur. J. Pharmacol. 151:151-154, 1988; George et al., Brain Res. 440:35-379, 1988; Choi, Brain Res. 403:333-336, 1987; Goldberg et al., Neurosci. Ltts. 80:11-15, 1987; Prince and Feeser, Neurosci. Ltts. 85:291-296, 1988; Feeser et al., Neurosci. Ltts. 86:340-345, 1988; Steinberg et al., Neurosci. Ltts. 89:193-197, 1988). Additional CNS actions may also arise from the metabolism of dextromethorphan to dextrorphan within the CNS by the cytochrome P450IID6 like enzyme localized in brain tissue (Fonne-Pfister et al., Biochem. Biophys. Res. Commun. 148:1144-1150, 1987; Niznik et al., Arch. Biochem. Biophys. 26:424-432, 1990).
In spite of the potentially desirable CNS activity of dextromethorphan, very little dextromethorphan is capable of reaching the CNS because of its extensive first-pass elimination in humans (Vetticaden et al., Pharmaceut. Res. 6:13-19, 1989; Ramachander et al., J. Pharm. Sci. 66:1047-1048, 1977). Without the administration of massive doses of dextromethorphan (&gt;750 mg/day) on a frequent basis, one cannot hope to overcome the efficient elimination of dextromethorphan in most subjects (Walker and Hunt, Clin. Neuropharmacol. 12:322-330, 1989). As a further complication, one also faces the nonlinearity in dextromethorphan elimination at higher doses. This may make individualization of therapy more difficult and the formation of toxic metabolites and/or adverse drug effects more likely (Walker and Hunt, Clin. Neuropharmacol. 12:322-330, 1989).
The large first-pass elimination of dextromethorphan is accounted for primarily by its O-demethylation to dextrorphan (Vetticaden et al., Pharmaceut. Res. 6:13-19, 1989; Koppel et al., Arzneim.-Forsch. Drug Res. 37:1304-1306, 1987). This metabolite is then rapidly conjugated and eliminated in the urine. The small amounts of dextromethorphan and dextrorphan which reach the CNS are primarily responsible for its antitussive properties. The efficient elimination of dextromethorphan and dextrorphan along with their relatively short half-lives, however, limits their effectiveness and utility for treating neurological disorders.
Accordingly, there is a need for the identification of pharmacologically active compounds that can inhibit the O-demethylation of dextromethorphan to dextrorphan and thereby, preclude the use of excessive dosing with dextromethorphan, with its accompanying problems. Such pharmacologically active compounds can only increase the effectiveness of dextromethorphan and dextrorphan as neuroprotective drugs.